EP0067608B1 - CRF et analogues - Google Patents

CRF et analogues Download PDF

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Publication number
EP0067608B1
EP0067608B1 EP82302812A EP82302812A EP0067608B1 EP 0067608 B1 EP0067608 B1 EP 0067608B1 EP 82302812 A EP82302812 A EP 82302812A EP 82302812 A EP82302812 A EP 82302812A EP 0067608 B1 EP0067608 B1 EP 0067608B1
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Prior art keywords
leu
glu
gln
ala
lys
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German (de)
English (en)
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EP0067608A1 (fr
Inventor
Wylie Walker Vale, Jr.
Joachim Spiess
Catherine Laure Rivier
Jean Edouard Frederick Rivier
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Salk Institute for Biological Studies
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Salk Institute for Biological Studies
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/57509—Corticotropin releasing factor [CRF] (Urotensin)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention is directed to peptides related to the hentetracontapeptide CRF and to the methods for pharmaceutical treatment of mammals using such peptides. More specifically, the invention relates to CRF and analogs of CRF, to pharmaceutical compositions containing CRF or such analogs and to methods of treatment of mammals using CRF or such analogs.
  • hypothalamus plays a key role in the regulation of adenohypo- physial corticotropic cells secretory functions.
  • Guillemin, Rosenberg and Saffran and Schally independently demonstrated the presence of factors in hypothalamus which would increase the rate of ACTH secretion by the pituitary gland incubated in vitro or maintained in an organ culture.
  • None of the secretagogs characterized to date meets the criteria expected of a physiologic corticotropin releasing factor, CRF. Accordingly the purification of a large CRF has been pursued.
  • Sauvagine es a 40-residue, amidated generally similar peptide which was isolated from the skin of the South American frog Phyllomedusa sauva- gei, was characterized by Erspamer et al. and was described in Regulatory Peptides, Vol. 2 (1981 pp. 1-13. Sauvagine has the formula:
  • Sauvagine has been reported to have biological activity in lowering blood pressure in mammals and in stimulating the secretion of ACTH and ⁇ -endorphin.
  • Analogs of the 41-residue peptide CRF having the following formula have at least substantially the same biological activity:
  • compositions in accordance with the invention include CRF or its analogs, or nontoxic addition salts thereof, dispersed in a pharmaceutically acceptable liquid or solid carrier.
  • administration of such peptides or pharmaceutically acceptable addition salts thereof to mammals in accordance with the invention may be carried out for the regulation of secretion of ACTH, ( ⁇ -endorphin, ⁇ -lipotropin, and corticosterone and/or for the lowering of blood pressure and/or for affecting mood, behavioral and gastrointestinal functions.
  • CRF has been isolated from ovine hypothalamic extracts purified and characterized.
  • the nomenclature used to define the peptides is that specified by Schroder & Lubke, 'The Peptides', Academic Press (1965) wherein, in accordance with conventional representation, the amino group appears to the left and the carboxyl group to the right. Where the amino acid residue has isomeric forms, it is the L-form of the amino acid that is represented unless otherwise expressly indicated.
  • the invention provides CRF and analogs of CRF having the following formula:
  • the peptides are synthesized by a suitable method, such as by exclusively solid-phase techniques, by partial solid-phase techniques, by fragment condensation or by classical solution addition.
  • CRF and certain analogs may also be synthesized by recently developed recombinant DNA techniques.
  • the sulfur When Met is present, the sulfur may be protected, if desired, with oxygen.
  • the imidazole nitrogen can be protected with Tos or 2,4-dinitrophenyl(DNP).
  • the hydroxyl group When Tyr is present, the hydroxyl group may be protected with DCB.
  • a side chain amino protecting group is not critical except that it must be one which is not removed during deprotection of the a-amino groups during the synthesis. Hence, the a-amino protecting groups and the side chain amino protecting group cannot be the same.
  • X 7 is selected from the class consisting of OH, OCH 3 , amides, hydrazides, esters and an amide anchoring bond used in solid phase synthesis for linking to a solid resin support, represented by the formulae:
  • the polyamide polymer is commerically available and is discussed in detail in Bioorganic Chemistry, 8, 351 - 370 (1979) where a preferred version of it is discussed in Figure 6.
  • Use of BHA or MBHA resin is preferred, and cleavage gives the CRF amide or CRF analog amide.
  • At least one of Xt, X2, X3, X4, X5 and X 6 is a protecting group.
  • they may also have a protecting group attached as specified hereinbefore and as generally known in the art and mentioned hereinbefore.
  • the protecting group In selecting a particular side chain protecting group to be used in the synthesis of the peptides, the following rules are followed: (a) the protecting group must be stable to the reagent and under the reaction conditions selected for removing the a-amino protecting group at each step of the synthesis, (b) the protecting group must retain its protecting properties and not be split off under coupling conditions and (c) the side chain protecting group must be removable, upon the completion of the synthesis containing the desired amino acid sequence, under reaction conditions that will not alter the peptide chain.
  • acyl group represented by Z acetyl, formyl, acrylyl and benzoyl are preferred.
  • 1 to 10 amino acid peptide which may be optionally included without adversely affecting the potency, any amino acids may be used, but the L- or D- forms of the naturally occurring amino acids would normally be used.
  • the peptides are preferably prepared using solid phase synthesis, such as that described by Merrifield, J. Am. Chem. Soc., 85, p. 2149 (1964), although other equivalent chemical syntheses known in the art can also be used as previously mentioned.
  • Solid-phase synthesis is commenced from the C-terminal end of the peptide by coupling a protected a-amino acid to a suitable resin as generally set forth in U.S. Patent No. 4,244,946 issued Jan. 21, 1981 to Rivier et al., the disclosure of which is incorporated herein by reference.
  • Such a starting material for CRF can be prepared by attaching a-amino-protected Ala to a BHA resin.
  • a-amino protecting group is removed, as by using trifluoroacetic acid(TFA) in methylene chloride, TFA alone or with HCI in dioxane.
  • TFA trifluoroacetic acid
  • 50 weight %TFA in methylene chloride is used with 0-5 weight % 1,2-ethanedithiol.
  • the deprotection is carried out at a temperature between about 0°C and room temperature.
  • Other standard cleaving reagents and conditions for removal of specific a-amino protecting groups may be used as described in Schroder & Lubke, 'The Peptides', 1 pp. 72-75 (Academic Press 1965).
  • the remaining a-amino- and side chain- protected amino acids are coupled step-wise in the desired order to obtain the intermediate compound defined hereinbefore.
  • each aminoacid separately in the synthesis, some of them may be coupled to one another prior to addition to the solid phase reactor.
  • the selection of an appropriate coupling reagent is within the skill of the art. Particularly suitable as a coupling reagent is N,N'-dicyclohexyl carbodiimide (DCCI).
  • activating reagents used in the solid phase synthesis of the peptides are well known in the peptide art.
  • suitable activating reagents are carbodiimides, such as N,N'-diisopropyl carbodiimide and N-ethyl-N ' -(3-dimethylaminopropyl)carbodiimide.
  • Other activating reagents and their use in peptide coupling are described by Schroder & Lubke, supra, in Chapter I-II and by Kapoor, J. Phar. Sci., 59, pp. 1-27 (1970).
  • Each protected amino acid or amino acid sequence is introduced into the solid phase reactor in about a fourfold excess, and the coupling is carried out in a medium of dimethylformamide(DMF):CH 2 CI 2 (1:1) or in DMF or CH Z CI Z alone.
  • the coupling is carried out manually, the success of the coupling reaction at each stage of the synthesis is monitored by the ninhydrin reaction, as described by E. Kaiser et al., Anal. Biochem. 34, 595 (1970).
  • the coupling procedure is repeated before removal of the a-amino protecting group prior to the coupling of the next amino acid.
  • the coupling reactions can be performed automatically, as on a Beckman 990 automatic synthesizer, using a program such as that reported in Rivier et al., Biopolymers, 1978,17, pp. 1927-1938.
  • the intermediate peptide is removed from the resin support by treatment with a reagent, such as liquid hydrogen fluoride, which not only cleaves the peptide from the resin but also cleaves all remaining side chain protecting groups X 2 , X 3 , X 4 , X 5 and X 6 and the a-amino protecting group X 1 (unless it is an acyl group which is intended to be present in the final peptide), to obtain the peptide.
  • a reagent such as liquid hydrogen fluoride
  • anisole and methylethyl sulfide are included in the reaction vessel as scavengers.
  • the BOC protecting group may be cleaved with trifluoroacetic acid(TFA)/ethanedithiol prior to cleaving the peptide from the resin to eliminate S-alkylation.
  • Example sets forth the preferred method for synthesizing analogs of CRF by the solid-phase technique.
  • the peptide chain is built step-by-step on the resin. Generally, one to two mmol. of BOC-protected amino acid in methylene chloride is used per gram of resin, plus one equivalent of 2 molar DCCI in methylene chloride, for two hours.
  • BOC-Arg(Tos) is being coupled, a mixture of 50% DMF and methylene chloride is used. Bzl is used as the hydroxyl side-chain protecting group for Ser and Thr.
  • P-nitrophenyl ester(ONp) is used to activate the carboxyl end of Asn or Gin, and for example, BOC-Asn(ONp) is coupled overnight using one equivalent of HOBt in a 50% mixture of DMF and methylene chloride.
  • the amido group of Asn or Gin is protected by Xan when DCC coupling is used instead of the active ester method.
  • 2-CI-Z is used as the protecting group for the Lys side chain.
  • Tos is used to protect the guanidino group of Arg and the imidazole group of His, and the side chain carboxyl group of Glu or Asp is protected by OBzl.
  • the peptide is purified by gel permeation followed by semi-preparative HPLC as described in Rivier et al., Peptides: Structure and Biological Function (1979) pp. 125-128. The chromatographic fractions are carefully monitored by HPLC, and only the fractions showing substantial purity were pooled.
  • Amino acid analyses of the hydrolysates using a Beckman 121 MB amino acid analyzer showed the following amino acid ratios: Asp(4.02), Thr(1.85), Ser(2.76), Glu(7.0), Pro(1.58), Ala(4.03), Val(0.96), Met(0.95), lle(1.93), Leu(8.15), Phe(1.00), Lys(2.00), His(1.95) and Arg(1.98), which confirmed that the 41-residue peptide structure had been obtained.
  • CRF was extracted, isolated and purified in the following manner. 490,000 ovine hypothalamic fragments were extracted in ethanol-acetic acid- chloroform, defatted with a mixture of ethyl ether and petroleum ether and subjected to repeated shake-out with the partition system 0.1% acetic acid: n-butanol: pyridine (11:5:3). the combined aqueous phases show ACTH-releasing activity.
  • the sample was applied in 0.01 M ammonium formate buffer, pH 3.2 and eluted with a linear gradient of the application buffer to 1:5 M ammonium formate, pH 7.0.
  • ACTH releasing activity was weakly absorbed.
  • the ACTH releasing fraction from SP-Sephadex and the remainder of the zone from Sephadex-G-50 were dissolved in 6 M guanidine HCI/HOAc, pH 2.5, heated 5 min. at 90°, then chromatographed on Biogel P-10 with 4 M guanidine HCI/HOAc, ph 2.5.
  • the ACTH-releasing fractions were pooled and purified further by successive high pressure liquid chromatographic (HPLC) steps which included: 1) Reverse phase HPLC on Bondapak CN (Waters and Associates) using a gradient of decreasing triethylammonium phosphate (TEAP) and increasing acetonitrile; 2) Reverse phase HPLC on Bondapak C 18 (Waters and Associates) with TEAP/acetonitrile; and either 3a) Reverse phase HPLC on Bondapak CN with gradients of triethylammonium formate and acetonitrile, or 3b) Reverse phase HPLC on C 18 with gradients of trifluoroacetic acid and acetonitrile. Lyophilized active zones from both HPLC steps 3a or 3b were used for composition and structural analysis which gave the following sequence:
  • the synthetic and the natural CRF were examined for their effects on the secretion of ACTH and ⁇ -endorphin in vitro and the synthetic CRF was also examined in vivo.
  • the high potency of synthetic and natural CRF to stimulate the secretion of ACTH and ⁇ -endorphin by cultured rat pituitary cells was measured.
  • Minimal and half- maximal responses were observed at about 10 picomolar and about 100 picomolar of synthetic CRF, respectively.
  • the secretory response to maximal (>5nM) concentrations of CRF is at a plateau level.
  • In vivo doses from 30 ng to 3 ⁇ g/kg of body weight rapidly elevated ACTH and ⁇ -endorphin-like ( ⁇ -END-LI) secretion 5-20 fold.
  • Synthetic CRF has been shown to be a powerful stimulator of ACTH and ⁇ -END-LI secretion in vivo in several rat preparations.
  • Plasma levels of ACTH and ⁇ -END-LI are elevated for at least 5-20 minutes following the intravenous administration of CRF to nembutal-anesthesized male rats and to quiescent male or female rats with indweling intravenous cannulae.
  • CRF is found to have a dramatic effect upon blood pressure in rats and dogs.
  • the peptide [des Ser 1 -Gln 2 -GIu 3 ]-CRF having the formula:
  • CRF and its analogs exhibited such an extreme lowering of blood pressure.
  • these peptides may be particularly valuable for the treatment of high blood pressure conditions and also for the treatment of patients who are to undergo certain types of surgery.
  • CRF cerebral spastic axis
  • CRF or its analogs should be useful to stimulate the functions of this axis in some types of patients with low endogenous glucocorticoid production.
  • CRF should be useful in restoring pituitary-adrenal function in patients having received exogenous glucocorticoid therapy whose adrenalcortical functions remain suppressed.
  • CRF may also find application in modifying the mood and behavior of normal and mentally disordered individuals. Because CRF and its analogs elevate the levels of ACTH, ⁇ -END, P-lipotropin and corticosterone, its administration can be used to induce their effects on the brain and its periphery to thereby influence memory, mood, pain appreciation, etc., and more specifically, alertness, depression and/or anxiety.
  • CRF CRF
  • GnRH superagonists inhibit reproductive functions.
  • these peptides may be able to desensitize CRF target organs and thus be valuable in the treatment of subjects with Cushing's disease and similar disorders.
  • CRF CRF
  • its analogs or the nontoxic addition salts thereof, combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition may be administered to mammals, including humans, either intravenously, subcutaneously, intramuscularly, intranasally, intra- cerebrospinally or orally.
  • the peptides should be at least about 93% pure and preferably should have a purity of at least about 98%. This purity means that the intended peptide constitutes the stated weight % of all like peptides and peptide fragments present.
  • Their administration may be employed by a physician to lower blood pressure or to stimulate endogenous gluco-corticoid production. The required dosage will vary with the particular condition being treated, with the severity of the condition and with the duration of desired treatment.
  • Such peptides are often administered in the form of pharmaceutically acceptable nontoxic salts, such as acid addition salts or metal complexes, e.g., with zinc, iron, calcium, barium, magnesium, aluminium or the like (which are considered as addition salts for purposes of this application).
  • acid addition salts are hydrochloride, hydrobromide, sulphate, phosphate, tannate, pamoate, oxalate, fumarate, gluconate, alginate, maleate, acetate, citrate, benzoate, succinate, malate, ascorbate, tartrate and the like.
  • the tablet may contain a binder, such as tragacanth, corn starch or gelatin; a disintegrating agent, such as alginic acid; and a lubricant, such as magnesium stearate.
  • a binder such as tragacanth, corn starch or gelatin
  • a disintegrating agent such as alginic acid
  • a lubricant such as magnesium stearate.
  • sweetening and/or flavoring may be used, and intravenous administration in isotonic saline, phosphate buffer solutions or the like may be effected.
  • the peptides should be administered under the guidance of a physician, and pharmaceutical compositions will usually contain the peptide in conjunction with a conventional, pharmaceutically-acceptable carrier. Usually, the dosage will be from about 1 to about 200 micrograms of the peptide per kilogram of the body weight of the host.
  • treatment of subjects with these peptides can be carried out in lieu of the administration of ACTH or corticosteroids, in such instances a dosage as low as about 10 ng/kg of body weight may be employed.
  • a dosage as low as about 10 ng/kg of body weight may be employed.
  • all temperatures are °C and all ratios are by volume. Percentages of liquid materials are also by volume.

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Claims (12)

1. Un composé ayant pour formule:
Z-R1-Pro-Pro-Ile-Sér-R8-Asp-Leu-R11-R12-R13-Leu-Leu-Arg-R17-R18-R19-Glu-R21-R22-Lys-R24-R25-R26-R27R28-Gln-Gln-Ala-R32-R33-Asn-Arg-R36-Leu-Leu-Asp-R40-R41-NH2
ou un sel d'addition non toxique correspondant; où Z est un groupe acyle ayant 7 atomes de carbone ou moins ou un hydrogène; R1 est Sér-Gln-Glu ou pGlu-Gly ou Gln-Glu ou Glu ou D-Sér-Gln-Glu ou D-pGlu-Gly ou dés R1; R8, R12, R19, R24 et R40 sont choisis parmi le groupe constitué par Leu, Ile, Ala, Gly, Val, Nle, Phé et Gln; R11 est Thr ou Sér; R13 est His, Tyr ou Glu; R17 est Glu ou Lys; R18 est Val ou Mét; R21 est Mét, Mét(O), lie, Ala, Leu, Gly, Nle, Val, Phé ou Gin; R22 est Thr ou Glu; R25 est Asp ou Glu; R26 est Gln ou Lys; R27 est Leu, Ile, Ala, Gly, Val, Nle, Phé, Asp, Asn, Gln ou Glu; R28 est Ala ou Lys; R32 est His, Tyr ou Ala; R33 est Sér, Asn, Thr ou Ala; R36 est Lys ou Leu; R41 est Ala, Ile, Gly, Val, Leu, Nie, Phé, Gln ou dés R41, sous réserve cependant que lorsque R13 est His, alors R17 est Glu, R18 est Val, R22 est Thr, R26 est Gln, R28 est Ala et R36 est Lys; et sous réserve que lorsque R13 est Glu, R17 est Lys, R18 est Mét, R22 est Glu, R26 est Lys, R28 est Lys, R32 est Ala et R36 est Leu, alors soit R1 n'est pas pGlu-Gly, soit R8 n'est pas Ile, soit R11 est Thr, soit R12 n'est pas Leu, soit R19 n'est pas Ile, soit R21 n'est pas lie, soit R24 n'est pas Gln, soit R27 n'est pas Glu, soit R33 n'est pas Asn, soit R40 n'est pas Thr, soit R41 n'est pas Ile et sous réserve de plus que Z peut éventuellement comprendre 1 à 10 amino-acides.
2. Le composé de la revendication 1, dans lequel R13 est His.
3. Le composé de la revendication 1, dans lequel R13 estTyr.
4. Le composé de la revendication 2 ou 3, dans lequel R25 est Glu.
5. Le composé de la revendication 2 ou 3, dans lequel R25 est Asp.
6. Le composé de la revendication 1, dans lequel R11 est Thr, R13 est His, R21 est Mét et R36 est Lys.
7. Le composé de la revendication 1 ayant pour formule:
H-Sér-Gln-Glu-Pro-Pro-Ile-Sér-Leu-Asp-Leu-Thr-Phé-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Mét-Thr-Lys-Ala-Asp-Gln-Leu-Ala-Gln-Gln-Ala-His-Sér-Asn-Arg-Lys-Leu-Leu-Asp-Ile-Ala-NH2 et étant pur au moins à environ 93%.
8. Le composé de la revendication 1, ayant pourformule:
H-Pro-Pro-Ile-Sér-Ile-Asp-Leu-Sér-Leu-Glu-Leu-Leu-Arg-Lys-Mét-Ile-Glu-Ile-Glu-Lys-Gln-Glu-Lys-Glu-Lys-Gln-Gln-Ala-Ala-Asn-Asn-Arg-Leu-Leu-Leu-Asp-Thr-Ile-NH2.
9. Un composé comme revendiqué dans la revendication 1, et essentiellement comme précédemment identifié spécifiquement relativement aux exemples I à XVIII.
10. Une composition pharmaceutique comprenant un composé comme revendiqué dans l'une quelconque des revendications 1 à 9, avec un support ou diluant permettant que la composition puisse être administrée par voie orale, intraveineuse, souscutanée, intranasale, intracépha- lorachidienne ou intramusculaire.
11. Un intermédiaire de peptide ayant pour formule:
X1-Sér(X2)-Gln(X4)-Glu(X5)-Pro-Pro-Ile-Sér (X2)-Leu-Asp(X5)-Leu-Thr(X2)-Phé-His(X8)-Leu-Leu-Arg(X3)-Glu(X5)-Val-Leu-Glu(X5)-Mét(O)-Thr (X2)-Lys(X6)-Ala-Asp(X5)-Gln(X4)-Leu-Ala-Gln (X4)-Gln(X4)-Ala-His(X8)-Sér(X2)-Asn(X4)-Arg (X3)-Lys(X6)-Leu-Leu-Asp(X5)-Ile-Ala-(X7) dans laquelle
X1 est un hydrogène ou un groupe α-amino-protecteur;
X2 est un hydrogène ou un groupe protecteur du groupe hydroxy alcoolique d'un reste Sér ou Thr; X3 est un hydrogène ou un groupe protecteur du groupe guanidino de Arg;
X4 est un hydrogène ou un groupe protecteur du groupe amido de Gln ou Asn;
X5 est un hydrogène ou un groupe protecteur du groupe carboxy de Asp ou Glu;
X6 est un hydrogène ou un groupe protecteur du groupe amino de la chaîne latérale de Lys; X7 est choisi parmi la catégorie constituée par OH, OCH3, les esters, les amides, les hydrazides,
-0-CH2-résine support de polystyrène et -O-CH2-aenzyl-résine support de polystyrène; et X8 est un hydrogène ou un groupe protecteur de l'azote de l'imidazole de His; sous réserve que tous les symboles X1 à X8 ne soient pas un hydrogène ou OH.
EP82302812A 1981-06-08 1982-06-01 CRF et analogues Expired EP0067608B1 (fr)

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AT82302812T ATE6505T1 (de) 1981-06-08 1982-06-01 Crf und analoge.

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US27162481A 1981-06-08 1981-06-08
US271624 1981-06-08

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EP0067608A1 EP0067608A1 (fr) 1982-12-22
EP0067608B1 true EP0067608B1 (fr) 1984-03-07

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Publication number Priority date Publication date Assignee Title
EP0518391A1 (fr) * 1984-02-23 1992-12-16 The Salk Institute For Biological Studies Analogues du CRF
CA1341051C (fr) * 1988-09-23 2000-07-11 Jean Edouard Frederic Rivier Antagonistes du crf
ZA898329B (en) * 1988-11-14 1990-07-25 Salk Inst For Biological Studi Fish crf
US5235036A (en) * 1991-05-31 1993-08-10 The Salk Institute For Biological Studies Crf analogs
DE4110422A1 (de) * 1991-03-29 1992-10-01 Bissendorf Peptide Gmbh Arzneimittel enthaltend humanes corticotropin-releasing hormon (crh) und/oder dessen derivate und/oder glucocorticoide natuerlicher und/oder synthetischer provenienz
US5830866A (en) * 1994-09-12 1998-11-03 The Trustees Of The University Of Pennsylvania Corticotropin release inhibiting factor and methods of using same
US6039956A (en) * 1994-09-12 2000-03-21 Pennsylvania, Trustees Of The University Of, The Corticotropin release inhibiting factor and methods of using same for treating behavioral symptoms in an anxiety disorder
KR102259056B1 (ko) 2017-12-29 2021-06-01 (주)에스엠테크 디아민 화합물과 알루미네이트계 화합물을 포함하는 광물 미분쇄용 분쇄조제 조성물 및 이를 사용한 광물의 미분쇄방법
JP7294312B2 (ja) 2018-02-16 2023-06-20 Jnc株式会社 重合性化合物、重合性組成物、重合体及びフォトレジスト用組成物

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JPS642600B2 (fr) 1989-01-18
NZ200711A (en) 1986-02-21
ZA823635B (en) 1983-03-30
AU8445582A (en) 1982-12-16
CA1243301A (fr) 1988-10-18
ES512892A0 (es) 1983-12-01
DK156957C (da) 1990-03-19
IL65937A0 (en) 1982-09-30
IE821330L (en) 1982-12-08
AU554676B2 (en) 1986-08-28
GR75679B (fr) 1984-08-02
ATE6505T1 (de) 1984-03-15
ES8401446A1 (es) 1983-12-01
KR890002774B1 (ko) 1989-07-28
DE3260057D1 (en) 1984-04-12
PH20364A (en) 1986-12-04
EP0067608A1 (fr) 1982-12-22
IL65937A (en) 1986-09-30
IE53488B1 (en) 1988-11-23
JPS57212149A (en) 1982-12-27
DK156957B (da) 1989-10-23
DK254982A (da) 1982-12-09
KR840000477A (ko) 1984-02-22

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